Methods and compositions for treating depression and other disorders using optically pure (-)-bupropion

ABSTRACT

Methods and compositions are disclosed utilizing the optically pure (−)-isomer of bupropion, which is a potent drug for treating depression, Parkinson&#39;s disease, obesity, weight gain and other disorders.

FIELD OF THE INVENTION

[0001] This invention relates to methods of treatment and pharmaceuticalcompositions employing the compound (−)-bupropion.

BACKGROUND OF THE INVENTION 2.1. Steric Relationships and Drug Action

[0002] Many organic compounds exist in optically active forms, i.e.,they have the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes (+) and (−) or d and l are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or l meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these compounds, called stereoisomers, are identical exceptthat they are mirror images of one another. A specific stereoisomer mayalso be referred to as an enantiomer, and a mixture of such isomers isoften called an enantiomeric or racemic mixture.

[0003] Stereochemical purity is of importance in the field ofpharmaceuticals, where 16 of the 20 most prescribed drugs exhibitchirality. A case in point is provided by the L-form of the β-adrenergicblocking agent, propranolol, which is known to be 100 times more potentthan the D-enantiomer.

[0004] Furthermore, optical purity is important since certain isomersmay actually be deleterious rather than simply inert. For example, ithas been suggested that the D-enantiomer of thalidomide was a safe andeffective sedative when prescribed for the control of morning sicknessduring pregnancy, while the corresponding L-enantiomer was a potentteratogen.

[0005] Bupropion is available only as a racemic mixture calledWellbutrin® and Wellbutrin SR® (for depression), and Zyban® (to achievesmoking cessation). That is, bupropion is available as a mixture ofoptical isomers, called enantiomers. The racemic mixture of bupropionwhich is commercially available is administered as a hydrochloride salt.In addition, European Patent Application No. 84101070.5 published Sep.12, 1984 discloses the benefits of bupropion maleate over bupropionhydrochloride.

[0006] Bupropion is used primarily in the treatment of depression, whichalong with mania, falls under the heading of affective disorders.Particularly, bupropion is used in patients who do not respond to, orcannot tolerate other antidepressants, such as the tricyclic agents ormonoamine oxidase inhibitors. Additionally, the racemic mixture ofbupropion is useful in the management of patients with bipolar andschizo-affective disorder, attention-deficit disorder, psycho-sexualdysfunction, bulimia and other eating disorders, and Parkinson'sdisease.

[0007] Affective disorders, including major depression, and the bipolar,manic-depressive illness, are characterized by changes in mood as theprimary clinical manifestation. Major depression is the most common ofthe significant mental illnesses, and it must be distinguishedclinically from periods of normal grief, sadness and disappointment, andthe related dysphoria or demoralization frequently associated withmedical illness. Depression is characterized by feelings of intensesadness, and despair, mental slowing and loss of concentration,pessimistic worry, agitation, and self-deprecation. Physical changes canalso occur, including insomnia, anorexia, and weight loss, decreasedenergy and libido, and disruption of hormonal circadian rhythms. Oftenthe condition responds well to tricyclic or related antidepressantdrugs, monoamine oxidase inhibitors, or in resistant cases or severedisease, to electro-convulsive shock treatment.

[0008] Mania, as well as depression, is characterized by changes in moodas the primary symptom. Either of these two extremes of mood may beaccompanied by psychosis with disordered thought and delusionalperceptions. Psychosis may have, as a secondary symptom, a change inmood, and it is this overlap with depression that causes much confusionin diagnosis. Severe mood changes without psychosis frequently occur indepression and are often accompanied by anxiety.

[0009] Through an unknown mechanism of action, bupropion has beendemonstrated to be an effective treatment in depression in short-termand longer duration clinical studies. The racemic mixture of bupropionhas been reported to have an antidepressant activity equal toamitriptyline, the tricyclic antidepressant, with fewer anticholinergic,sedative and cardiovascular side effects than with amitriptyline.

[0010] Parkinson's disease, independent of a specific etiology, is achronic, progressive central nervous system disorder which usuallyappears insidiously in the latter decades of life. The disease producesa slowly increasing disability in purposeful movement. It ischaracterized by four major clinical features of tremor, bradykinesia,rigidity and a disturbance of posture. Often patients have anaccompanying dementia. In idiopathic Parkinsonism, there is usually aloss of cells in the substantia nigra, locus ceruleus, and otherpigmented neurons of the brain, and a decrease of dopamine content innerve axon terminals of cells projecting from the substantia nigra. Theunderstanding that Parkinsonism is a syndrome of dopamine deficiency andthe discovery of levodopa as an important drug for the treatment of thedisease were the logical culmination of a series of related basic andclinical observations, which serves as the rationale for drug treatment.

[0011] When the racemic mixture of bupropion is used to treatParkinson's disease, an improvement in gait, akinesia, and posturalstability were observed, with tremor improving in those patientsexperiencing the most global benefit. Concomitant depression wasalleviated in several of the patients reporting the condition.

[0012] Attention-deficit disorder (“ADD”) is a common behaviorallearning disorder in children which adversely affects school performanceand family relationships. Symptoms and signs include hyperactivity(e.q., ADDH and AD/HD, DSM-IV), impulsivity, emotional lability, motorincoordination and some perceptual difficulties. Treatment has includedpsychostimulants, which while effective are controversial, and may causetroubling side effects such as dysphoria, headache and growthretardation. Other drugs, including the tricyclic antidepressants,appear to improve attention, but may be less effective than thepsychostimulants.

[0013] Bupropion has been shown to be effective in children withattention-deficit disorder or conduct disorder thus improving thesymptoms of anxiety, hostility and uncooperativeness, antisocialbehavior, as well as eating disturbances. The drug has also demonstratedactivity in cases of psycho-sexual dysfunction and bulimia. However,bupropion is contra-indicated in patients with a seizure disorder, or acurrent or prior diagnosis of bulimia or anorexia nervosa characterizedby a disturbed sense of body image and abnormally high anxiety aboutweight gain.

[0014] It has been suggested that the racemic mixture of bupropion couldbe used to assist in weight loss. Treatment with bupropion isconsistently associated with a lack of weight gain. Also bupropionreduces episodes of binge eating and purging. Although the mechanism bywhich bupropion causes weight loss is uncertain, an increase in theactivity of the patient may play some part together with subtle changesin food intake and metabolism.

[0015] The causes of excess body weight and/or obesity are complex;however, a common denominator in the overweight person's diet is acaloric intake which exceeds that person's body expenditures. One methodof treating a person who is overweight and/or obese is to restrict thatperson's caloric intake, in combination with an exercise regimen. Thismethod may be limited in its effectiveness since many overweight orobese people have developed eating and activity patterns which arecounterproductive to achieving weight reduction. Another method to treatoverweight or obese patients is to administer appetite suppressant drugsin conjunction with a weight reduction program. The drawback to thismethod is that many appetite suppressant drugs produce undesirableadverse effects which limit their usefulness.

[0016] The racemic mixture of bupropion, in addition to its use in thetreatment of depression and the other above-mentioned disorders, hasbeen shown to have a wide spectrum of action which includes:

[0017] Treatment of the effects of ethanol (U.S. Pat. No. 4,393,078)

[0018] Treatment of Tardine Dyskinesia (U.S. Pat. No. 4,425,363)

[0019] Treatment of Minimal Brain Dysfunction (U.S. Pat. No. 4,435,449)

[0020] Treatment of amelioration of prostate hypertrophy and sexualdysfunction (U.S. Pat. No. 4,835,147)

[0021] Treatment of psychostimulant addiction (U.S. Pat. No. 4,935,429)

[0022] Treatment of Psychosexual Dysfunction (U.S. Pat. No. 4,507,323)

[0023] Methods of Reducing Cholesterol (U.S. Pat. No. 4,438,138)

[0024] Methods of assisting weight loss (U.S. Pat. No. 4,895,845)

[0025] The racemic mixture of bupropion has been shown to have certainadvantages over other antidepressant drugs. For example, bupropion doesnot inhibit monoamine oxidase, or block the reuptake of serotonin. Attherapeutic concentrations, the compound presumably does not bind toadrenergic, dopamine, GABA, histamine, muscarinic, serotonin, orimipramine binding sites. While its specific neurochemicalantidepressant action is unknown, it does have a relatively weak effecton blocking the reuptake of dopamine, and it appears to reducenorepinephrine metabolism.

[0026] While the racemic mixture of bupropion has advantages, it alsohas disadvantages. Among these disadvantages are adverse effects inaddition to those described above. The most serious adverse effectassociated with the racemic mixture of bupropion is the increasedincidence of seizures. In addition, other frequently reported adverseeffects associated with the use of racemic bupropion include nausea,vomiting, excitement, agitation, blurred vision, restlessness, posturaltremor, and some hallucinations/confusional states with the potentialfor abuse. Other adverse or side effects associated with the racemicmixture of bupropion include but are not limited to anxiety, insomnia,headaches and/or migraines, dry mouth, constipation, tremor, sleepingdisturbances, dermatologic problems (e.g., rashes), neuropsychiatricsigns and symptoms (e.g., delusions and paranoia), and weight loss orgain. See, the Physician's. Desk Reference® (1998). These effects aredose limiting in a number of patients. In Parkinsonian patients, theadverse effects can be the particular toxicity of the racemic mixture ofbupropion, or the result of a drug interaction (as most patients werereceiving concomitant levodopa).

[0027] Thus, it is desirable to find a compound with the advantages ofthe racemic mixture of bupropion without the above-describeddisadvantages.

SUMMARY OF THE INVENTION

[0028] The active compound of compositions and methods disclosed hereinis an optical isomer of the compound bupropion which is described inU.S. Pat. Nos. 3,819,706 and 3,885,046. Chemically, this isomer is(−)-2-(tertbutylamino)-3'-chloropropiophenone or(−)-1-(3-chlorophenyl)-2[(1,1-dimethyl-ethyl)amino]-1-propanone. Thisisomer will hereinafter be referred to as “(−)-bupropion”, which alsoincludes the substantially optically pure (−)-bupropion isomer.

[0029] It has now been discovered that the optically pure (−)-isomer ofbupropion is an effective antidepressant which is useful in treatingdepression in humans. In accordance with the present invention,(−)-bupropion can be used to treat depression while avoiding adverseeffects including but not limited to seizures, agitation, dry mouth,insomnia, headache/migraine, nausea, dizziness, tachycardia, vomiting,constipation, and tremor associated with the racemic mixture ofbupropion. It has also been discovered that (−)-bupropion andpharmaceutical compositions containing optically pure (−)-bupropion areuseful in treating weight gain or obesity. Furthermore, it has beendiscovered that the optically pure (−)-isomer of bupropion is useful inthe treatment of Parkinson's disease. In addition, it has been foundthat the optically pure (−)-isomer of bupropion is useful in thetreatment of other disorders including but not limited to bipolardisorders, attention-deficit disorders, conduct. disorders,psycho-sexual dysfunction, bulimia, eating disorders and specific foodcravings.

[0030] The present invention also includes methods for treating theabove-described conditions in a human while avoiding adverse effectsthat are associated with the racemic mixture of bupropion, byadministering the optically pure (−)-isomer of bupropion to said human.

DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention encompasses a method of treating depressionin a human while avoiding the concomitant liability of adverse effectsassociated with the administration of racemic. bupropion which comprisesadministering to said human in need of antidepressant therapy, an amountof (−)-bupropion or a pharmaceutically acceptable salt thereof,substantially free of its (+)-stereoisomer, said amount being sufficientto alleviate depression, but insufficient to cause adverse effectsassociated with racemic bupropion.

[0032] The present invention also encompasses pharmaceuticalcompositions for the treatment of humans which comprises atherapeutically effective amount of (−)-bupropion or a pharmaceuticallyacceptable salt thereof, substantially free of its (+)-stereoisomer, anda pharmaceutically acceptable carrier. Preferred pharmaceuticalcompositions are those which have a means for controlled sustainedrelease of the active ingredient, (−)-bupropion.

[0033] The present invention further encompasses a method of treatingParkinson's disease in a human while avoiding the concomitant liabilityof adverse effects associated with the administration of racemicbupropion, which comprises administering to said human suffering fromParkinson's disease, an amount of (−)-bupropion, or a pharmaceuticallyacceptable salt thereof, substantially free of its (+)-stereoisomer,said amount being sufficient to alleviate said condition, butinsufficient to cause adverse effects associated with administration ofracemic bupropion.

[0034] Further, the present invention encompasses a method of treatingobesity or weight gain in a human, which comprises administering to saidhuman in need of a reduction in weight, an amount of (−)-bupropion or apharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer, said amount being sufficient to reduce weight orprevent weight gain, but insufficient to cause adverse effectsassociated with administration of racemic bupropion.

[0035] The present invention also encompasses a method of treatingdisorders including, but not limited to, bipolar disorders,attention-deficit disorders, conduct disorders, psycho-sexualdysfunction, bulimia, eating disorders and specific food cravings inhumans while avoiding the concomitant liability of adverse affectsassociated with the administration of racemic bupropion, which comprisesadministering to a human in need of such therapy a therapeuticallyeffective amount of (−)-bupropion, or a pharmaceutically acceptable saltthereof, substantially free of its (+)-stereoisomer.

[0036] The racemic mixture of bupropion (i.e., approximately a 50:50mixture of its two enantiomers) causes antidepressant activity andprovides therapy and/or reduction of symptoms in a variety of conditionsand disorders; however, this racemic mixture, while offering theexpectation of efficacy, causes a broad range of adverse effects.Utilizing the optically pure (−)-isomer of bupropion results in clearerdose-related definitions of efficacy, diminished adverse effects,and-accordingly an improved therapeutic index. It is therefore, moredesirable to use the (−)-isomer of bupropion for the conditionsdescribed herein.

[0037] The term “adverse effects” as used herein includes, but is notlimited to seizures, dry mouth, insomnia, dizziness, restlessness,anxiety, agitation, headache/migraine, nausea/vomiting, constipation,tremor, delusions, tachycardia, hallucinations, psychotic episodes,blurred vision, confusion, paranoia, rashes and sleep disturbances.

[0038] The term “substantially free of the (+)-stereoisomer” as usedherein means that the composition contains a greater proportion of the(−)-isomer of bupropion in relation to the (+)-isomer of bupropion. In apreferred embodiment the term “substantially free of its (+)-isomer” asused herein means that the composition contains at least 90% by weightof (−)-bupropion and 10% by weight or less of (+)-bupropion; or morepreferably about 95% by weight of (−)-bupropion and 5% or less of its(+)-isomer. These percentages are based on the total amount of bupropionpresent in the composition. In the most preferred embodiment the term“substantially free of the (+)-stereoisomer” means that the compositioncontains approximately 99% by weight of (−)-bupropion, and 1% or less ofthe (+)-bupropion. In another preferred embodiment, the term“substantially free of its (+)-stereoisomer” as used herein means thatthe composition contains greater than 99% by weight of the (−)-isomer ofbupropion, again based on the total amount of bupropion present. Theterms “substantially optically pure (−)-isomer of bupropion,” “opticallypure (−)-isomer of bupropion” and “(−)-isomer of bupropion” are alsoencompassed by the above-described amounts.

[0039] The term “a method of treating depression” as used herein meansrelief from the symptoms of depression which include, but are notlimited to changes in mood, feelings of intense sadness and despair,mental slowing, loss of concentration, pessimistic worry, agitation, andself-deprecation. Physical changes may also be relieved, includinginsomnia, anorexia and weight loss, decreased energy and libido, and thereturn of normal hormonal circadian rhythms.

[0040] The term “attention deficit disorder” (ADD) and “attentiondeficit disorder with hyperactivity” (ADDH), DSM-III, or attentiondeficit/hyperactivity disorder (AD/HD), DSM-IV are used herein mean inaccordance with the accepted meanings.

[0041] The term “treating Parkinson's disease” as used herein meansrelief from the symptoms of Parkinson's disease which include, but arenot limited to tremor, bradykinesia, rigidity, and a disturbance ofposture.

[0042] The term “treating obesity or weight gain in a human” as usedherein means reduction of weight or relief from being overweight orgaining weight due to extensive consumption of food and other factorsincluding metabolism disorders.

4.1. Synthesis of Optically Pure Bupropion

[0043] The synthesis of the (−)-isomer of bupropion may start fromreadily available 3-chloropropiophenone (1). Reaction of (1) with a(2R,3R)-(+)-dialkyl tartrate such as (+)-dimethyl or diethyl tartrate inthe presence of an acid catalyst such as methanesulfonic acid gives thechiral acetal (2) according to Castaldi (G. Castaldi, et al., J. Org.Chem. 1987, 52: 3018). Steroselective bromination with bromine in carbontetrachloride, or alternatively ethyl acetate, then produces thecorresponding bromoacetal (3) as the major product according to theabove-referenced procedure developed by Castaldi and co-workers. Thebromoacetal (3) is purified by column chromatography to yield theoptically pure bromoacetal (3) which is then hydrolyzed in the presenceof an acid to afford the bromoketone (4). Treatment of the bromoketone(4) with tert-butylamine, followed by reaction with anhydrous hydrogenchloride, then produces optically pure (−)-bupropion hydrochloride (5)after recrystallization. See the scheme below.

[0044] Alternatively, the optically pure isomers of bupropion can beprepared asymmetrically according to the procedures reported by Musso etal., “Synthesis and Evaluation of the Antidepressant Activity of theEnantiomers of Bupropion”, Chirality 5:495-500 (1993) which isincorporated herein by reference in its entirety.

[0045] In addition to the above-described methods the stereoisomers ofbupropion may be obtained by resolutions of a mixture of enantiomers ofbupropion using conventional means such as an optically active resolvingagent; see, for example, “Stereochemistry of Carbon Compounds”, by E. L.Eliel (McGraw-Hill, NY, 1962), and S. H. Wilen, p. 268 in “Tables ofResolving Agents and Optical Resolutions” (E. L. Eliel, Ed., Univ. ofNotre Dame Press, Notre Dame, Ind., 1972).

[0046] The magnitude of a prophylactic or therapeutic dose of(−)-bupropion in the acute or chronic management of disease will varywith the severity of the condition to be treated and its route ofadministration. The dose and dose frequency will also vary according tothe age, weight, condition and response of the individual patient. Ingeneral, the recommended daily dose range for the conditions describedherein lies within the range of from about 10 mg to about 750 mg perday, generally divided equally into doses given three or four times aday. Preferably, a daily dose range should be between 50 mg and 600 mgper day, usually divided equally into a three or four times a daydosing. Most preferably, a daily dose range should be between 60 mg and450 mg per day, usually divided equally into a three times or a fourtimes a day dosing. It may be necessary to use dosages outside theseranges in some cases. The physician will know how to increase, decreaseor interrupt treatment based upon patient response. The various termsdescribed above such as “said amount being sufficient to alleviate saiddepression”, “said amount being sufficient to alleviate said condition”when said condition is Parkinson's Disease, “said amount beingsufficient to reduce weight or weight gain”, “said amount beingsufficient to achieve weight loss” and “therapeutically effectiveamount” are encompassed by the above-described dosage amounts and dosefrequency schedule.

[0047] Any suitable route of administration may be employed forproviding the patient with an effective dosage of (−)-bupropion. Forexample, oral, rectal, parenteral, transdermal, subcutaneous,intrathecal, intramuscular and the like may be employed as appropriate.Dosage forms include tablets, coated tablets, caplets, capsules,troches, dispersions, sustained release formulations, suspensions,solutions, patches and the like.

[0048] The pharmaceutical compositions of the present invention comprisethe (−)-isomer of bupropion as active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids including inorganic acidsand organic acids.

[0049] Since the compound of the present invention is basic, salts maybe prepared from pharmaceutically acceptable non-toxic acids includinginorganic and organic acids. Such acids include maleic, acetic,benzene-sulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Particularly preferred arehydrobromic, hydrochloric, phosphoric, and sulfuric acids.

[0050] The pharmaceutical compositions of the present invention includecompositions suitable for oral, rectal, and parenteral administration(including subcutaneous, intrathecal, intramuscular, and intravenous),although the most suitable route in any given case will depend on thenature and severity of the condition being treated. The most preferredroute of the present invention is the oral route. They may beconveniently presented in unit dosage form and prepared by any of themethods well-known in the art of pharmacy.

[0051] In the case where an oral composition is employed, a suitabledosage range for use is, e.g., from about 10 mg to about 750 mg per day,generally divided equally into a three times a day dosing, preferablyfrom about 50 mg to about 600 mg per day, generally divided equally intoa three times a day dosing and most preferably-from about 60 mg to about450 mg per day, generally divided equally into a three times a daydosing. Patients may be upward titrated from below to within this doserange to a satisfactory control of symptoms as appropriate.

[0052] In practical use, (−)-bupropion can be combined as the activeingredient in intimate admixture with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques. The carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g., oral or parenteral (includingintravenous injections or infusions). In preparing the compositions fororal dosage form, any of the usual pharmaceutical media may be employed,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, for example, suspensions, elixirs and solutions; oraerosols; or carriers such as starches, sugars, microcrystallinecellulose, stabilizers, diluents, granulating agents, lubricants,binders, fillers, disintegrating agents and the like in the case of oralsolid preparations such as, powders, capsules and tablets, with thesolid oral preparations being preferred over the liquid preparations.The preferred solid oral preparation is tablets. The most preferredsolid oral preparation is coated tablets. Because of their ease ofadministration tablets and capsules represent the most advantageous oraldosage unit form, in which case solid-pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

[0053] Pharmaceutical stabilizers may also be used to stabilizecompositions containing (−)-bupropion or salts thereof; acceptablestabilizers including but are not limited to L-cysteine hydrochloride,glycine hydrochloride, malic acid, sodium metabsulfite, citric acid,tartaric acid and L-cysteine dihydrochloride. See, e.g., U.S. Pat. No.5,358,970 which is incorporated herein by reference.

[0054] In addition to the common dosage forms set out above, thecompounds of the present invention may also be administered bycontrolled release or sustained release means and/or delivery devicessuch as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 3,630,200, 4,008,719, 4,687,660, and 4,769,027,the disclosures of which are hereby incorporated by reference. Preferredcontrolled release or sustained released tablets for use with(−)-bupropion are described in U.S. Pat. No. 5,427,798 which isincorporated herein by reference.

[0055] Pharmaceutical compositions of the present invention suitable fororal administration may be presented as discrete units such as capsules,cachets, or tablets or aerosol sprays, each containing a predeterminedamount of the active ingredient, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, filler,lubricant, inert diluent, and/or surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent. Desirably,each tablet contains from about 10 mg to about 250 mg of the activeingredient, and each cachet or capsule contains from about 10 mg toabout 250 mg of the active-ingredient. Most preferably, the tablet,cachet or capsule contains one of four dosages: about 50 mg, about 75mg, about 100 mg and about 150 mg of active ingredient.

[0056] The invention is further defined by reference to the followingexamples describing in detail the preparation of the compound andcompositions of the present invention. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the purpose andinterest of this invention.

[0057] All temperatures are in degrees Celsius.

EXAMPLES 5.1. Example 1 Oral Formulation

[0058] Coated Tablets: Formula Quantity per Tablet (mg.) (−)-bupropion75 Lactose 125 Corn Starch 5.0 Water (per thousand Tablets) 30.0 ml*Magnesium Stearate 0.5 Corn Starch 25.0

[0059] The active ingredient is blended with the lactose until a uniformblend is formed. The smaller quantity of corn starch is blended with asuitable quantity of water to form a corn starch paste. This is thenmixed with said uniform blend until a uniform wet mass is formed. Theremaining corn starch is added to the resulting wet mass and mixed untiluniform granules are obtained. The granules are then screened through asuitable milling machine, using a ¼ inch stainless steel screen. Themilled granules are then dried in a suitable drying oven until thedesired moisture content is obtained. The dried granules are then milledthrough a suitable milling machine using ¼ mesh stainless steel screen.The magnesium stearate is then blended and the resulting mixture iscompressed into tablets of desired shape, thickness, hardness anddisintegration. Tablets are coated by standard aqueous or nonaqueoustechniques.

5.2. Example 2 Oral Formulation

[0060] Capsules: Quantity per capsule in mg. Formula A B C Activeingredient 25 50 75 (−)-bupropion Lactose 149.5 124.5 374 Corn Starch 2525 50 Magnesium Stearate 0.5 0.5 1.0 Compression Weight 200.0 200.0500.0

[0061] The active ingredient, (−)-bupropion, lactose, and corn starchare blended until uniform; then the magnesium stearate is blended intothe resulting powder. The resulting mixture is encapsulated intosuitably sized two-piece hard gelatin capsules.

5.3. Example 3 Oral Formulation

[0062] Tablets Quantity per capsule in mg. Formula A B C Activeingredient, 20 40 100 (−)-bupropion lactose BP 134.5 114.5 309.0 starchBP 30.0 30.0 60.0 Pregelatinized Maize 15.0 15.0 30.0 Starch BPmagnesium stearate 0.5 0.5 1.0 Compression Weight 200.0 200.0 500.0

[0063] The active ingredient is sieved through a suitable sieve andblended with lactose, starch, and pregelatinized maize starch. Suitablevolumes of purified water are added and the powders are granulated.After drying, the granules are screened and blended with the magnesiumstearate. The granules are then compressed into tablets using punches.

[0064] Tablets of other strengths may be prepared by altering the ratioof active ingredient to lactose or the compression weight and usingpunches to suit.

5.4. Example 4

[0065] Sustained Release Formulation (Tablet) FORMULA QUANTITY PERTABLET (mg) (−)-bupropion hydrochloride 100 Contramid ® crosslinkedamylose 98.8 Cysteine hydrochloride 7.5 Magnesium stearate 1.2

[0066] (−)-Bupropion Hydrochloride is formulated using Contramid®(Labopharm, Inc, Quebec) technology. The formulation is prepared byblending the ingredients above (dry) and compressing into tablets.Alternatively, the ingredients can be formulated using wet granulationtechnology known in the art. (See Example 1).

5.5. Example 5

[0067] Sustained Release Formulation (Tablet) FORMULA QUANTITY PERTABLET (mg) Contramid ® crosslinked amylose 98.8 Cysteine hydrochloride7.5 (−)-bupropion hydrochloride 75 Magnesium stearate 1.2

[0068] (−)-Bupropion Hydrochloride is formulated using Contramid®(Labopharm, Inc, Quebec), technology. The formulation is prepared byblending the ingredients above (dry) and compressing into tablets.Alternatively, the ingredients can be formulated using wet granulationtechnology known in the art. (See Example 1).

5.6. Example 6

[0069] FORMULA QUANTITY PER TABLET (mg) (−)-bupropion hydrochloride 150Diffutab ® hydrophilic 100 polymer mixture Microcrystalline cellulose100 Cysteine hydrochloride 7.5 Magnesium stearate 4

[0070] (−)-Bupropion Hydrochloride is formulated using Diffutab®(Eurand, Microencapsulation, S.A. of Switzerland) technology. Theformulation components are dry blended and directly compressed intotablets or formulated using wet granulation technology.

[0071] The embodiments of the present invention described above areintended to be merely exemplary and those skilled in the art willrecognize, or be able to ascertain using no more than routineexperimentation, numerous equivalents to the specific proceduresdescribed herein. All such equivalents are considered to be within thescope of the present invention and are covered by the following claims.

[0072] The contents of all references described herein are herebyincorporated by reference.

[0073] Other embodiments are within the following claims.

What is claimed is:
 1. A method of treating depression in a human whileavoiding the concomitant liability of adverse effects associated withadministration of racemic bupropion, which comprises administering to ahuman in need of antidepressant therapy, a therapeutically effectiveamount of (−)-bupropion or a pharmaceutically acceptable salt thereof,substantially free of its (+)-stereoisomer.
 2. The method of claim 1wherein said amount is sufficient to alleviate said depression, butinsufficient to cause said adverse effects associated withadministration of racemic bupropion.
 3. The method of claim 1 wherein(−)-bupropion is administered intravenously, transdermally or orally. 4.The method of claim 3 wherein (−)-bupropion is administered orally as atablet or a capsule.
 5. The method of claim 1 wherein the amountadministered is from about 10 mg to about 750 mg.
 6. The method of claim5 wherein the amount administered is from about 50 mg to about 600 mg.7. The method of claim 6 wherein the amount administered is from about60 mg to about 450 mg.
 8. The method of claim 1 wherein the amount of(−)-bupropion or a pharmaceutically acceptable salt thereof is greaterthan approximately 90% by weight of the total amount of bupropion. 9.The method of claim 1 wherein the amount of (−)-bupropion or apharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer is administered together with a pharmaceuticallyacceptable carrier.
 10. The method according to claim 1 wherein(−)-bupropion is administered as the hydrochloride salt.
 11. The methodof claim 1 wherein (−)-bupropion is administered in a sustained orcontrolled release formulation.
 12. A method of treating Parkinson'sdisease in a human while avoiding the concomitant liability of adverseeffects associated with the administration of racemic bupropion, whichcomprises administering to said human in need of treatment forParkinson's disease, a therapeutically effective amount of (−)-bupropionor a pharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer.
 13. The method of claim 12 wherein said amount issufficient to alleviate said Parkinson's disease, but insufficient tocause said adverse effects associated with administration of racemicbupropion.
 14. The method of claim 12 wherein (−)-bupropion isadministered by intravenously, transdermally, or orally.
 15. The methodof claim 14 wherein (−)-bupropion is administered orally as a tablet ora capsule.
 16. The method of claim 12 wherein the amount administered isfrom about 10 mg to about 750 mg.
 17. The method of claim 16 wherein theamount administered is from about 50 mg to about 600 mg.
 18. The methodof claim 17 wherein the amount administered is from about 60 mg to about450 mg.
 19. The method of claim 12 wherein the amount of (−) -bupropionor a pharmaceutically -acceptable salt thereof is greater thanapproximately 90% by weight of the total amount of bupropion.
 20. Themethod of claim 12 wherein the amount of (−)-bupropion or apharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer, is administered together with a pharmaceuticallyacceptable carrier.
 21. The method according to claim 12 wherein(−)-bupropion is administered as the hydrochloride salt.
 22. The methodof claim 12 wherein (−)-bupropion is administered in a sustained orcontrolled release formulation.
 23. A method for treating obesity orweight gain in a human which comprises administering to a human in needof weight reduction or weight control a therapeutically effective amountof (−)-bupropion or a pharmaceutically acceptable salt thereof,substantially free of its (+)-stereoisomer.
 24. The method of claim 23wherein said amount is sufficient to alleviate obesity or weight gain,but insufficient to cause adverse effects associated with administrationof racemic bupropion.
 25. The method of claim 23 wherein (−)-bupropionis administered by intravenously, transdermally, or orally.
 26. Themethod of claim 25 wherein (−)-bupropion is administered orally as atablet or a capsule.
 27. The method of claim 23 wherein the amountadministered is from about 10 mg to about 750 mg.
 28. The method ofclaim 27 wherein the amount administered is from about 50 mg to about600 mg.
 29. The method of claim 28 wherein the amount administered isfrom about 60 mg to about 450 mg.
 30. The method of claim 23 wherein theamount of (−)-bupropion or a pharmaceutically acceptable salt thereof isgreater than approximately 90% by weight of the total amount ofbupropion.
 31. The method of claim 23 wherein the amount of(−)-bupropion or a pharmaceutically acceptable salt thereof,substantially free of its (+)-stereoisomer, is administered togetherwith a pharmaceutically acceptable carrier.
 32. The method according toclaim 23 wherein (−)-bupropion is administered as the hydrochloridesalt.
 33. The method of claim 23 wherein (−)-bupropion is administeredin a sustained release or controlled release formulation.
 34. A methodof treating a disorder selected from the group consisting of bipolardisorders, attention-deficit disorders, conduct disorders, psycho-sexualdysfunction, bulimia, eating disorders and specific food craving whichcomprises administering to a human suffering from said disorder atherapeutically effective amount of (−)-bupropion, or a pharmaceuticallyacceptable salt therefore, substantially free of its (+)-stereoisomer.35. The method of claim 34 wherein (−)-bupropion is administered byintravenously, transdermally, or orally.
 36. The method of claim 35wherein (−)-bupropion is administered orally as a tablet or a capsule.37. The method of claim 34 wherein the amount administered is from about10 mg to about 750 mg.
 38. The method of claim 37 wherein the amountadministered is from about 50 mg to about 600 mg.
 39. The method ofclaim 38 wherein the amount administered is from about 60 mg to about450 mg.
 40. The method of claim 34 wherein the amount of (−)-bupropionor a pharmaceutically acceptable salt thereof is greater thanapproximately 90% by weight of the total amount of bupropion.
 41. Themethod of claim 34 wherein the amount of (−)-bupropion or apharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer, is administered together with a pharmaceuticallyacceptable carrier.
 42. The method according to claim 34 wherein(−)-bupropion is administered as the hydrochloride salt.
 43. The methodof claim 34 wherein (−)-bupropion is administered in a controlled orsustained release formulation.
 44. A pharmaceutical composition whichcomprises a therapeutically amount of (−)-bupropion or apharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer, and a pharmaceutically acceptable carrier.
 45. Thecomposition according to claim 44 wherein the amount is about 10 mg toabout 750 mg.
 46. The composition according to claim 44 which comprises(−)-bupropion hydrochloride.
 47. The composition according to claim 46wherein said composition is adapted for oral administration.
 48. Thecomposition according to claim 46 adapted for intravenous delivery. 49.The composition according to claim 46 for use in a transdermalformulation.
 50. The composition according to claim 46 for use as atransdermal patch.
 51. The composition of claim 46 wherein saidcomposition is a solid preparation.
 52. A sustained release formulationwhich comprises (−)-bupropion or a pharmaceutically acceptable saltthereof substantially free of its (+)-stereoisomer, and apharmaceutically acceptable carrier.
 53. The sustained releaseformulation of claim 52 wherein said formulation is a tablet, capsule orgelcap.